Patch containing fentanyl for mucous membrane of oral cavity

ABSTRACT

To provide a patch containing fentanyl for mucous membrane of the oral cavity (oral transmucosal fentanyl), which rapidly increases the serum concentration of the drug, is easy in handling and is superior in safety. The patch can be prepared by laminating on one side of a drug layer which contains fentanyl or its salt as an active ingredient, methyl vinyl ether-maleic anhydride copolymer as an adhesive, and at least one substance selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose as a thickener, a support layer hardly soluble or insoluble in water, and a backing in this order.

TECHNICAL FIELD

The present invention relates to a patch containing fentanyl for mucousmembrane of the oral cavity (oral transmucosal fentanyl), which issuperior in handling on application (pasting), rapidly increases theserum concentration of the drug, is a little in transfer of the drug toa gastrointestinal tract, is easily tore off when it becomesunnecessary, and is superior in safety.

Namely, the present invention relates to the patch containing fentanylfor mucous membrane of the oral cavity, which can be prepared bylaminating a drug-layer which contains fentanyl or its salt as an activeingredient and shows adhesivity due to being dissolved in or swelledwith water, a support layer hardly soluble or insoluble in water, and abacking in their order.

BACKGROUND ART

Fentanyl or its citrate is a synthetic narcotic analgesic whoseanalgesic activity is about 100 times higher than that of morphine inthe animal test.

Nowadays, the transdermally absorbable and sustained release preparationcontaining fentanyl for the therapy of cancer pain is commercialized andit retains almost the effective serum concentration for 24 to 72 hoursafter administration (see Japanese Patent Publication A 61-37725).However, in regard to said transdermally absorbable and sustainedrelease preparation, as the absorption of the drug is mild afteradministration of it, and the effective serum concentration can not beobtained until 12 to 24 hours after initial administration, it isimpossible to expect the quick analgesic effect. Furthermore, even aftersaid transdermally absorbable and sustained release preparation is toreoff from the skin, fentanyl remains in the corneum. Therefore, itsabsorption into body continues, the drug is hardly removed from thebody, and the half-life of the serum concentration is long, 17 hours. Assuch, said transdermally absorbable and sustained release preparation isnot suitable for the therapy for acute ache such as pang (breakthroughpain) which occurs while the preparation is continuously applied.Against such pang which occurs while said preparation being continuouslyapplied, the immediately active morphine preparations (injections, oralpreparations, suppositories) are additionally administered as arescue-preparation (a preparation for emergently additionaladministration) in Japan.

In regard to a transdermally absorbable preparation containing fentanyl,other various preparations are proposed (see Japanese Patent PublicationA 2000-44476, and Japanese Patent Publication A 10-45570).

On the other hand, the fentanyl preparation for mucous membrane of theoral cavity which is possible to quickly circulate through the wholebody and is noninvasively administered (Trade name: Actiq) is sold inUSA (see U.S. Pat. No. 4,671,953). This preparation is a candy-typepreparation with a stick (lollipop). When pang occurs, the preparationis put between cheek and submaxillary gingivae and is sucked in a periodof 15 minutes to absorb fentanyl citrate from mucous membrane of theoral cavity. The amount of the systemic transfer by absorption of thedrug from mucous membrane of the oral cavity is about one fourth. Therest of it is swallowed with saliva and is gradually absorbed from agastrointestinal tract. In regard to said preparation, the tip of thepreparation with a stick must be put between cheek and submaxillarygingivae for 15 minutes to give much uncomfortable feeling in a mouth.However, when it is chewed, the swallowed amount becomes much and theamount absorbed from mucosal membrane of the oral cavity becomes less.When pang disappears, the drug becomes unnecessary and theadministration of the drug is stopped. Even if the preparation is takenoff from the oral cavity in such a case, the drug which was alreadytransferred into a gastrointestinal tract continues to be absorbedthereafter. Therefore, it is difficult to control the serumconcentration of the drug.

In addition, patches containing fentanyl for mucous membrane of the oralcavity are described in Japanese Patent Publication A 2002-275066, etc.,but they are not yet put in practice.

DISCLOSURE OF INVENTION

The object of the present invention is to provide a patch containingfentanyl for mucous membrane of the oral cavity, which does not need anycomplex procedures when the patch is applied, gives a littleuncomfortable feeling in the oral cavity, can quickly increases theserum concentration as the drug is absorbed almost at the appliedregion, makes transfer of the drug into a gastrointestinal tract less bypreventing the drug release into other part of the oral cavity exceptthe applied region, is easily tore off when it becomes unnecessary, caneasily control the serum concentration of the drug, is usable as arescue preparation for pang during the therapy for cancer pain and ishighly safe.

The present invention relates to a patch containing fentanyl for mucousmembrane of the oral cavity, which can be prepared by laminating on oneside of a drug layer which contains fentanyl or its salt as an activeingredient, methyl vinyl ether-maleic anhydride copolymer as anadhesive, and at least one substance selected from the group consistingof hydroxypropyl cellulose, hydroxypropyl methylcellulose andhydroxyethyl cellulose as a thickener, a support layer hardly soluble orinsoluble in water, and a backing in their order.

The present inventors have been extensively studied in order to solvethe above problems and as a result have found that a drug layer whichcontains fentanyl or its salt as an active ingredient, methyl vinylether-maleic anhydride copolymer as an adhesive, and at least onesubstance selected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methylcellulose and hydroxyethyl cellulose as a thickenershows sufficient adhesivity to mucous membrane of the oral cavity due tothe presence of water and easily releases the drug from the appliedsurface and quickly increases the serum concentration. Furthermore, bylaminating a support layer which is insoluble or hardly soluble in wateron the opposite side of the adhesive surface of the drug layer, the drugis hardly swallowed with saliva due to protecting to release the druginto the other region in the oral cavity except the applied region, andfurthermore, by equipping a backing thereto and making the patch thickin some extend, regardless of smallness of the size, handling of thepatch becomes easy, such as picking up, applying or tearing off, andthat the patch containing fentanyl for mucous membrane of the oralcavity which is easily controllable the serum concentration is obtained.Thus the present invention has been completed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the cross section of a patch containing fentanyl for mucousmembrane of the oral cavity of the present invention.

FIG. 2 shows the test result on skin-permeability in vitro by using apreparation of Example 1 of the present invention.

FIG. 3 shows the test result on the permeability in the corneumremoved-skin by the stripping method in vitro by using preparations ofExamples 2 to 5 of the present invention.

FIG. 4 shows the test result on measurement of the serum concentrationof fentanyl after administration of a preparation of Example 4 of thepresent invention to mucous membrane of the oral cavity of dogs.

FIG. 5 is the test result of the drug release by using a preparation ofExample 5 of the present invention.

EXPLANATION OF SIGNS

-   -   1: Drug layer    -   2: Support layer    -   3: Backing    -   4: Liner

BEST MODE FOR CARRYING OUT THE INVENTION

The mode for carrying out the present invention is explained in detail.

The ingredients which are used and if necessary, other ingredients arecontained in the preparation of the present invention are explained indetail.

Fentanyl or its salt (the drug) which is contained in the drug layer ofthe preparation of the present invention is a free-base or an organic orinorganic salt thereof, such as fentanyl citrate, etc. Their combinationcan be also used, but fentanyl citrate is especially preferably used.

The amount of the drug is 0.01˜40 w/w % per total amount of the druglayer, preferably 2˜35 w/w %, and more preferably 5˜30 w/w %. When theamount is less than 0.01 w/w %, it is impossible to expect sufficientefficacy of the drug. When the amount is beyond 40 w/w %, and otheringredients consisting of the drug layer, the drug and the solvent aremixed, the insoluble materials remain and therefore, it is impossible toprepare the preparation.

The amount of methyl vinyl ether-maleic anhydride copolymer used as anadhesive in the drug layer of the preparation of the present inventionis 5˜90 w/w % per total weight of the drug layer, preferably 10˜70 w/w%, and more preferably 15˜60 w/w %.

When the amount is less than 5 w/w %, the adhesivity decreases and it isdifficult that the preparation maintains to stick to mucous membrane ofthe oral cavity, and when the amount is beyond 90 w/w %, the preparationbecomes fragile and becomes difficult to keep the shape. Therefore, suchamounts are not preferable.

The thickener used in the drug layer of the preparation of the presentinvention includes a cellulose derivative selected from the groupconsisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose andhydroxyethyl cellulose, or a combination thereof. Hydroxypropylcellulose is especially preferably used.

The amount of the thickener is 0.2˜80 w/w % per total amount of the druglayer, preferably 1˜60 w/w %, and more preferably 2.5˜50 w/w %. When theamount is less than 0.2 w/w %, the preparation becomes difficult to keepthe shape, and when the amount is beyond 80 w/w %, the preparationbecomes difficult to release the drug. Therefore such amounts are notpreferable.

A softening agent may be contained in the drug layer of the preparationof the present invention.

The softening agent includes, for example, glycerin, polyethylene glycol(PEG) 200, PEG 300, PEG 400, propylene glycol, etc., or a combinationthereof. A combination of glycerin and PEG 400 is especially preferablyused and the ratio is preferably 1:1 to 1:5. The amount is 0˜50 w/w %per the total amount of the drug layer, preferably 2˜40 w/w %, and morepreferably 5˜30 w/w %. When the amount is beyond 50 w/w %, the druglayer easily collapses and it is difficult that the preparationsufficiently maintains to stick to mucous membrane of the oral cavity.Therefore, such amounts are not preferable.

An absorption promoting agent, such as N-methyl-2-pyrrolidone may beadded to the drug layer in order to promote the absorption of the drugfrom mucous membrane of the oral cavity. The amount is 0˜10 w/w % perthe total amount of the drug layer, preferably 1˜7 w/w %. When theamount is beyond 10 w/w %, there is anxious for irritation to mucousmembrane of the oral cavity, the drug layer becomes easily collapsible,and it is difficult that the preparation sufficiently maintains to stickto mucous membrane of the oral cavity. Therefore, such amounts are notpreferable.

A sweetening agent may be contained in the drug layer of the preparationof the present invention in order to lessen the bitter taste, such asglycerin, glucose, fructose, maltose, sucrose, D-sorbitol, D-mannitol,xylitol, etc. The amount is 0˜30 w/w % per total amount of the druglayer, preferably 2˜20 w/w. When the amount is beyond 30 w/w %, the druglayer becomes easily collapsible and it is difficult that thepreparation sufficiently maintains to stick to mucous membrane of theoral cavity. Therefore, such amounts are not preferable.

In regard to the preparation of the present invention, the support layerwhich is insoluble or hardly soluble in water is laminated on the druglayer in order to prevent to release the drug in other part of the oralcavity except the applied region.

As a material which is contained in order to make the support layer thewater-insoluble or hardly water-soluble, ethyl cellulose is illustrated.The amount is 40˜90 w/w % per total amount of the support layer,preferably 50˜75 w/w %. When the amount is less than 40 w/w %, thewater-insolubility or hard water-solubility of the support layer greatlydecreases, and when the amount is beyond 90 w/w %, it is anxious thatthe affinity with the drug layer decreases and that the layers areseparated. Therefore, such amounts are not preferable.

In order to give the support layer of the present invention the affinityto the drug layer, a thickener can be further added thereto. Thethickener includes hydroxypropyl methylcellulose, especiallyhydroxypropyl methylcellulose 2910, and it can be solely used or in acombination of other hydroxypropyl methylcellulose. The amount is 1˜30w/w % per total amount of the support layer, preferably 5˜25 w/w %. Whenthe amount is less than 1 w/w %, it is anxious that the affinity withthe drug layer decreases and the layers are separated, and when theamount is beyond 30 w/w %, it becomes difficult to maintain thewater-insolubility or water-hardly solubility of the support layer.Therefore, such amounts are not preferable.

To the support layer, a plasticizer may be further added. Theplasticizer includes surfactants, such as castor oil, trietyl citrate,polysorbate, etc. The surfactant can be used solely or in a combinationof them, and especially castor oil can be preferably used. The amount is1˜50 w/w % per total weight of the drug layer, preferably 2˜35 w/w %,and more preferably 5˜30 w/w %. When the amount is less than 1 w/w %,the flexibility of the support layer decreases, and when the amount isbeyond 50 w/w %, the support layer becomes easily collapsible.Therefore, such amounts are not preferable.

As the backing of the preparation of the present invention, woven orunwoven fabrics, or paper can be used. When woven or unwoven fabrics areused, one or more fabrics selected from biodegradable plastics,polyester, polyethylene and polypropylene represented by aliphaticpolyester, such as poly lactic acid, poly glycolic acid, poly lactone,polybutylene succinate, are used, and especially fabrics consisting ofpoly lactic acid are preferably used.

The drug layer or the support layer of the preparation of the presentinvention may, if necessary, contain additives, such as a coloring agentlike red #102, yellow #4, titanium oxide, etc., a corrective like citricacid, povidone, menthol, etc., an antioxidant like ascorbic acid,disodium edatate, tocopherol acetate, etc., a stabilizer like lightsilicic acid anhydride, macrogol, etc., a preservative like sodiumbenzoate, parabens, etc.

The method for preparing the patch containing fentanyl for mucousmembrane of the oral cavity of the present invention is not limited, butfor example, the following steps are illustrated.

Ingredients contained in the drug layer, when they are liquid,themselves, or when they are solid or very highly viscous, after each ofthem is dissolved or dispersed in a suitable medium, are mixed understirring. The mixture is spread on a liner made of polyethyleneterephtalate, polypropylene, polyethylene, etc., dried and if necessary,spreading and drying are repeated several times. The procedure iscarried so that the thickness of the drug layer after finally dryingbecomes 20˜200 μm.

Next, when ingredients contained in the support layer are liquid, theyare mixed under stirring. When the ingredients are solid or highlyviscous, they are mixed under stirring, after each of them is dissolvedor dispersed in a suitable medium. The mixture is spread on the surfaceon the opposite side of the liner side of the drug layer. Then thereonis laminated the backing, and if necessary the laminate is stuck underthe pressure by a roller, and dried to prepare the preparation so as tohave the thicknesses of the support layer and the backing, respectively1˜200 μm and 50˜1000 μm. A part or all of ingredients of the supportlayer can be penetrated into the backing to incorporate with it. Ifnecessary, after the support layer is spread (coated), the drying andspreading may be repeated, but it is preferable to spread on the supportlayer once.

EXAMPLE

The present invention is explained by illustrating examples, but thepresent invention is not limited by these examples.

Example 1

According to ingredients of Example 1 shown in Table 1, a drug layer wasprepared. Namely, methyl vinyl ether-maleic anhydride copolymer in 80%ethanol, hydroxypropyl cellulose (Viscosity: 150˜400 mPa·S) in ethanol,glycerin, N-methyl-2-pyrrolidone and fentanyl citrate were mixed understirring. The mixture was spread (coated) on a liner made ofpolyethylene terephtalate and dried to prepare a film having 100 μm inthickness.

According to ingredients of Example 1 shown in Table 2, a support layerwas prepared. Namely, ethyl cellulose in ethanol, hydroxypropylmethylcellulose 2910 in 50% ethanol, a dispersion of titanium oxide inethanol and castor oil were mixed under stirring. The mixture was spreadon the surface on the opposite side of the liner side of the druglayer-film. Thereon were laminated unwoven fabrics made of poly lacticacid fiber having 410 μm in thickness as a backing, and the preparationwas dried to give an objected patch containing fentanyl for mucousmembrane of the oral cavity. The thickness of the support layer wasprepared as to be theoretically 25 μm in thickness.

Example 2

Ingredients for a drug layer of Example 2 shown in Table 1, ingredientsfor a support layer of Example 2 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 3

Ingredients for a drug layer of Example 3 shown in Table 1, ingredientsfor a support layer of Example 3 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 4

Ingredients for a drug layer of Example 4 shown in Table 1, ingredientsfor a support layer of Example 4 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 5

Ingredients for a drug layer of Example 5 shown in Table 1, ingredientsfor a support layer of Example 5 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 6

Ingredient for a drug layer of Example 6 shown in Table 1, ingredientsfor a support layer of Example 6 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 7

Ingredient for a drug layer of Example 7 shown in Table 1, ingredientsfor a support layer of Example 7 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 8

Ingredient for a drug layer of Example 8 shown in Table 1, ingredientsfor a support layer of Example 8 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

Example 9

Ingredients for a drug layer of Example 9 shown in Table 1, ingredientsfor a support layer of Example 9 shown in Table 2 and a backing werelaminated in the same manner as in Example 1 to prepare an objectedpatch containing fentanyl for mucous membrane of the oral cavity.

TABLE 1 Ingredient Example (weight %) 1 and 8 2 3 4 5 and 9 6 7 Fentanylcitrate 19 19 19 19 19 19 19 Methyl vinyl 43 43 43 43 43 55 21ether-maleic anhydride copolymer Hydroxypropyl — — — — 21.5 15 —cellulose (Viscosity: 6~10 mPa · S) Hydroxypropyl 21.5 21 — 21.5 — — 40cellulose (Viscosity: 150~400 mPa · S) Hydroxypropyl — — 21 — — — —cellulose (Viscosity: 1000~4000 mPa · S) Glycerin 2.5 3 7.5 7.5 7.5 37.5 Polyethylene 12.5 12 7.5 7.5 7.5 6 7.5 glycol 400 N-Methyl-2- 1.5 22 1.5 1.5 2 5 pyrrolidone

TABLE 2 Example 1~7 8 9 Ingredient (weight %) Ethyl cellulose 66 66 70Hydroxypropyl 13.5 21 7 methylcellulose 2910 Castor oil 17 9.5 19.5Titanium oxide 3.5 3.5 3.5

Test 1

The skin-permeation test in vitro was carried out on the preparation ofExample 1 using the transdermally absorbable sustained releasepreparation as a control.

After removal of hairs of the abdomen of Wistar rats (6˜7 weeks, male),the skin was extracted. The body site of the skin was fit as a donorside on a Franz diffusion cell kept at 37° C. The patch containingfentanyl for mucous membrane of the oral cavity of Example 1 was punchedin a circle having 25 mm in diameter (containing fentanyl 9 mg).Physiological saline was sprayed on the surface of the drug layer of thecircle and the circle was stuck to the skin. The transdermallyabsorbable sustained release preparation containing 2.5 mg of fentanylwas stuck as a control in the same as the above. Phosphate buffer wasfilled in the receptor side and the sampling was carried out withvariation with time. The amount of fentanyl was measured by HPLC and thepermeated amount of fentanyl was calculated. The result was shown inFIG. 2.

The patch containing fentanyl for mucous membrane of the oral cavity ofExample 1 showed quick skin-permeability comparing with the preparationfor mucous membrane of the oral cavity as a control.

Test 2

The skin-permeation test in vitro on the preparations of Examples 2 to 5was carried out on the corneum removed-skin by stripping.

After removing hairs of the abdomen of Wistar rats (6˜7 weeks, male),this area was subjected to stripping 5 times by using an adhesive tapeand then the skin was extracted. The body site of the skin was fit as adonor side on a Franz diffusion cell kept at 37° C. Each of the patchescontaining fentanyl for mucous membrane of the oral cavity of Examples 2to 5 was punched in a circle having 25 mm in diameter (containingfentanyl 9 mg). Physiological saline was sprayed on the surface of thedrug layer of the circle and the circle was stuck to the skin. Phosphatebuffer was filled in the receptor side and the sampling was carried outwith variation with time. The amount of fentanyl was measured by HPLCand the permeated amount of fentanyl was calculated. The result wasshown in FIG. 3.

All patches containing fentanyl for mucous membrane of the oral cavityof Examples 2 to 5 showed high skin-permeability on the corneumremoved-skin.

Test 3

The serum concentration of fentanyl after applying the preparation ofExample 4 to mucous membrane of the oral cavity of a dog was measured.

A patch containing fentanyl for mucous membrane of the oral cavity ofExample 4 was punched in an ellipse having 2 cm² (containing fentanyl 3mg). Physiological saline was sprayed on the surface of the drug layerof the ellipse and then the ellipse was stuck to an inside of the upperlip of a beagle (weight 15˜19 kg, male). The blood was collected fromtime to time and fentanyl concentration in the serum was measured byHPLC. A patch containing fentanyl for mucous membrane of the oral cavity(containing fentanyl 2.5 mg) was stuck to the skin of the breast of thedog in the same as the above and the variation with time on the serumconcentration was compared with the former (see Kyles, et al., Americanjournal of veterinary research Vol. 57, No. 5, page 715˜719, 1996).

The result was shown in FIG. 4. Although the serum concentration mildlyrose in regard to the preparation for mucous membrane of the oral cavityas a control, the serum concentration quickly rose and dropped down andthe peak concentration was higher in regard to the patch containingfentanyl for mucous membrane of the oral cavity of Example 4.

Test 4

The drug release test was carried out on the preparation of Example 5.

A patch containing fentanyl for mucous membrane of the oral cavity ofExample 5 was punched in an ellipse having 2 cm² (containing fentanyl 3mg) and the backing-side of the ellipse was stuck on both sides of apaddle for an elution test tool with using a double-sided adhesive tape.Phosphate buffer 500 ml as an elution was put in a vessel and kept at37° C., and the paddle on which the patch containing fentanyl for mucousmembrane of the oral cavity stuck was set at the middle height of theelution and then the paddle was rotated at 50 rpm. At 5, 10, 20, 30 and60 minutes later after the test began, the elutions were taken, theamounts of fentanyl were measured by HPLC and the ratio of the drugrelease was calculated. As a control, the drug layer-side of the patchcontaining fentanyl for mucous membrane of the oral cavity was stuck onthe paddle, and the same test as the above was carried out. The resultwas shown in FIG. 5.

The drug release-rate of the patch containing fentanyl for mucousmembrane of the oral cavity of Example 5 from the side of the drug layerwas about 20% at 5 minutes later after initiation, about 50% at 30minutes later after initiation, and about 70% at 60 minutes later afterinitiation, and the quick drug release was observed. As a control, thedrug layer-side was stuck on the paddle and the drug release from thebacking-side was observed. The slowly rising on the drug release ratewas observed, but after 60 minutes, the drug release-rate became low,about one twentieth, and the drug release was considerably refrained dueto the support layer which was insoluble or hardly soluble.

INDUSTRIAL APPLICABILITY

According to the present invention, by using the drug layer whichcontains fentanyl or its salt as an active ingredient, methyl vinylether-maleic anhydride copolymer as an adhesive, and at least onesubstance selected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methylcellulose and hydroxyethyl cellulose as a thickener,can be obtained the preparation which shows sufficient adhesivity tomucous membrane of the oral cavity and can quickly increases the serumconcentration due to effectively releasing the drug from the appliedsurface.

Furthermore, by laminating the support layer which is insoluble orhardly soluble in water on the opposite side of the adhesive surface ofthe drug layer, the drug release into the other region except theapplied region and the drug-transfer into a gastrointestinal tract arelessen and when the patch does not need, a great part of the remaineddrug can be quickly removed by tearing off the patch.

Furthermore, by equipping the backing thereto and making it sufficientlythick, handling of the preparation becomes easy and its application toand its tearing off from mucous membrane of the oral cavity become easy.

As mentioned above, the patch containing fentanyl for mucous membrane ofthe oral cavity of the present invention can quickly increase the serumconcentration of fentanyl after application to mucous membrane of theoral cavity, and according to the necessity, can be removed andtherefore, the serum concentration is easily controlled and the patch isuseful for the rescue preparation on pang during the therapy for cancerpain.

1. A patch containing fentanyl for mucous membrane of the oral cavity,which comprises a drug layer, a support layer hardly soluble orinsoluble in water comprising ethyl cellulose and hydroxypropylmethylcellulose, on the drug layer, and a backing on the support layer,wherein the drug layer consists essentially of fentanyl or its salt asan active ingredient, methyl vinyl ether-maleic anhydride copolymer asan adhesive agent, and at least one substance selected from the groupconsisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose andhydroxyethyl cellulose as a thickener.
 2. The patch containing fentanylfor mucous membrane of the oral cavity according to claim 1, wherein thefentanyl salt is fentanyl citrate.
 3. The patch containing fentanyl formucous membrane of the oral cavity according to claim 1, wherein thedrug release rate from the drug layer is adjusted to become 50% withinone hour.
 4. The patch containing fentanyl for mucous membrane of theoral cavity according to claim 1, wherein the ratio of the adhesive andthe thickener is a range selected from 5:95 to 97:3.
 5. The patchcontaining fentanyl for mucous membrane of the oral cavity according toclaim 2, wherein the drug release rate from the drug layer is adjustedto become 50% within one hour.
 6. The patch containing fentanyl formucous membrane of the oral cavity according to claim 1, wherein thedrug layer consists of fentanyl or its salt as an active ingredient,methyl vinyl ether-maleic anhydride copolymer as an adhesive agent, atleast one substance selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose and hydroxyethyl cellulose as athickener, and further at least one member selected from the groupconsisting of a softening agent, an absorption promoting agent and asweetening agent.
 7. A patch containing fentanyl for mucous membrane ofthe oral cavity, which comprises a drug layer, a support layer hardlysoluble or insoluble in water comprising ethyl cellulose andhydroxypropyl methylcellulose, on the drug layer, and a backing on thesupport layer, wherein the drug layer consists of fentanyl or its saltas an active ingredient, methyl vinyl ether-maleic anhydride copolymeras an adhesive agent, and at least one substance selected from the groupconsisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose andhydroxyethyl cellulose as a thickener.
 8. A patch containing fentanylfor mucous membrane of the oral cavity, which comprises a drug layer, asupport layer hardly soluble or insoluble in water comprising ethylcellulose and hydroxypropyl methylcellulose, on the drug layer, and abacking on the support layer, wherein the drug layer consistsessentially of fentanyl or its salt as an active ingredient, methylvinyl ether-maleic anhydride copolymer as an adhesive agent, and atleast one substance selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose and hydroxyethyl cellulose as athickener and further at least one member selected from the groupconsisting of a softening agent selected from glycerin and polyethyleneglycol, an absorption promoting agent consisting ofN-methyl-2-pyrrolidone and a sweetening agent.